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Slide 1
Practical Management of interactions between DAA and ARVs
David Back University of Liverpool UK
David Back, Liverpool, UK
Paris: June 12th 2014
Disclosures
• Honoraria received from Gilead, Janssen, Merck, Abbvie, BMS, Boehringer-Ingelheim, Viiv.
• Research or Educational Grant support from Gilead, Janssen, Merck, Abbvie, Roche, Vertex, BMS, Boehringer-Ingelheim, Viiv.
• Presentation refers to the following unlabelled/unapproved drugs: faldaprevir, daclatasvir, asunaprevir, ledipasvir, ABT-450/r, ABT-267, ABT-333; MK-5172, MK-8742.
HCV DAAs: a success story of multiple disciplines.
Molecular Virology Deciphered the viral replication cycle and identified druggable
targets.
Structural Biology Provided high-resolution structures of viral targets – allowing
modelling of drug-target interactions
Molecular & Clinical Pharmacology Shown the disposition of compounds and developed
strategies to optimise therapies – in particular in relation to drug-drug interactions.
Multiple Clinical Trials Efficacy and AEs.
Anti-HCV drugs approved and in advanced development
Manns M & van Hahn Nature Rev Drug Discovery, 2013; 12: 595-610
Prueksaritanont T et al.
Preclinical
Studies identify drug ‘X’ as: i) Substrate of
enzyme or transporter,
ii) An inhibitor or inducer.
Healthy Volunteers
Targeted approach Predicts the nature of a DDI ie increase or decrease in exposure
Patient Population HCV
Fibrosis stage: F0, F1, F2, F3, F4. Altered expression/function of hepatic enzymes and/or transporters!
In 2011, telaprevir and boceprevir were licensed for use in HCV GT1 infection. The side effect profile of these drugs in combination with PEG IFNα and RBV are not favourable and the costs per SVR in patients with advanced hepatic fibrosis are such that they should ideally no longer be used in patients with HCV GT1 as soon as other, more efficacious, better tolerated, options are available.
Drug CYP 3A4 Transporters Non-CYP
metabolism
Telaprevir Metabolised
by Inhibits
Transported by P-gp Inhibits P-gp;
OATP1B1/2 –
Boceprevir Metabolised
by Inhibits
Transported by P-gp; BCRP
Inhibits P-gp; OCT1/2
AKR Metabolised
by
Telaprevir and Boceprevir Interactions: What have we learned?
P-gp: P-glycoprotein; AKR: aldo-keto reductase
CYP 3A isozymes are The most abundant CYP enzymes in the liver Involved in the metabolism of many drugs
Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102.
Importance of metabolism and transport in relation to systemic drug levels
Adapted from: Bailey DG, et al. CMAJ 2013;185:1066
Enterocytes
Hepatocytes drug
100%
1
2
CYP3A4
P-gp BCRP MRP2
OATP1A2 OATP2B1
CYP3A4
UGTs
OATP1B1 OATP1B3 OCT1
Enzyme/Transporter induction or inhibition
CYP 1A2 CYP 2A6 CYP 2B6
CYP 2C8 CYP 2C9
CYP 2C19 CYP 2D6
CYP 2E1 CYP 3A
If clearance of co-med involves just CYP3A4 – co-med levels increase.
But if other or additional metabolic pathways – co-med levels could decrease.
There may be other interaction mechanisms (eg transporter and protein binding displacement)
Telaprevir and Boceprevir Interactions: What have we learned?
ARVs cleared by CYP3A4: Maraviroc (major), Rilpivirine (major), Dolutegravir (minor) -
Predictable
Finding consistent with CYP3A inhibition Is increase in RPV exposure clinically significant? Note: No dose adjustment recommended.
De Kanter C et al CID 2013; 56: 300-306 van Heeswijk R et al; ICAAC 2011; Vourvahis M et al IWCPHT, 2013; Abs O-17
ARV exposure (AUC) Effect of TVR Effect of BOC
Maraviroc ↑ 9-fold ↑ 3-fold
Rilpivirine ↑ 78% ↑ 39%
Dolutegravir ↑ 37% ↑ 7%
Clin Pharm Review FDA Sept 2011 Eviplera SmPC 31/10/13
Why is exposure of boosted HIV PIs mainly decreased in healthy volunteer studies?
Effect of TVR & BOC on HIV Boosted PI concentrations
NOTE: RTV inhibits >90% of CYP3A activity so TVR & BOC exert other effects.
Effect of HIV Boosted on TVR & BOC concentrations
Complex enzyme – transporter interplay between the 3 components ie DAA, HIV PI, RTV; Also protein binding displacement or even absorption
effects.
Telaprevir (TVR) Boceprevir (BOC)
Atazanavir Monitor for bilirubin Consider; case-by-case
Darunavir Not recommended Not recommended
Efavirenz Increase to 1125 mg 3xday
Not recommended
Rilpivirine Recommended (but QT concerns)
Recommended
Etravirine Recommended Consider; case-by-case
Raltegravir Recommended Recommended
Dolutegravir Recommended Recommended
Known and predicted DDIs between TVR and BOC and key Anti HIV drugs
Modified from Karageorgopoulos DE et al Curr Opin Infect Dis 2014; 27: 36-45; www.hep-druginteractions.org
Are drug interactions different in HCV patients compared to healthy subjects?
Evidence that drug exposure in plasma of some DAAs is altered (note: hepatic impairment) Changes in protein binding in liver disease. Evidence that enzyme activity is altered in liver
disease Some evidence from co-infection that the
magnitude of an interaction may be different.
Effect of Mild or Moderate Hepatic Impairment on DAA PK
Drug Mild Moderate
Telaprevir AUC decreased 15% AUC decreased 46%A
Boceprevir No change AUC increased 14% (49% in severe)
Simeprevir AUC increased 2.4-fold
Sofosbuvir AUC increased 2.3-fold
Daclatasvir AUC decreased 43% AUC decreased 40%
Asunaprevir AUC decreased 21% AUC increased 9.8-fold
www.hep-druginteractions.org Data relative to normal liver function.
Are drug interactions different in HCV patients compared to healthy subjects? Evidence that drug exposure in plasma of some
DAAs is altered (note: hepatic impairment) Changes in protein binding in liver disease
Evidence that enzyme activity is altered in liver
disease Some evidence from co-infection that the
magnitude of an interaction may be different.
Daclatasvir
AUC of ARV Healthy Volunteers
HCV+ (16% cirrhotics)
ATV/r ↓ 35% ↓ 30%
DRV/r ↓ 44% ↓ 42%
EFV ↓ 20% ↓ 7%
RAL ↓ 4% ↑ 59%
15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy.
Sofosbuvir
SOF is activated in hepatocyte Hydrolases (CES1, Cat A; HNT1)
Phosphorylated to active GS-4612003
Predominant circulating form GS-331007
SOF not metabolised by or inhibits CYP SOF interacts with P-gp (and BCRP) - Victim
Sofosbuvir and P-gp Induction
• Potent P-gp inducers in the intestine (rifampicin, St. John's wort, carbamazepine and phenytoin) may significantly decrease sofosbuvir plasma concentration leading to reduced therapeutic effect. Sofosbuvir should not be co-administered with known inducers of P-gp.
• Other P-gp inducers eg modafanil – SPC not recommended; USPI – not mentioned.
Sovaldi SPc – accessed April 12th 2014
Effect of ARVs on Sofosbuvir: Victim
Drug Effect on Sofosbuvir and GS-331007 AUC (exposure) Recommendation
Darunavir/r
SOF increased 34%; GS-331007 – no effect
No dose adjustment
Rilpivirine
No effect on SOF or GS-331007 No dose adjustment
Efavirenz No effect on SOF or GS-331007 No dose adjustment
Raltegravir No effect on SOF or GS-331007: RAL decreased 27%
No dose adjustment
Tenofovir No effect on SOF or GS-331007
No dose adjustment
Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013
No known or anticipated interactions with antiretrovirals
Effect of Other Co-administered Drugs on Sofosbuvir: Victim
Drug Effect on Sofosbuvir and GS-331007 AUC (exposure) Recommendation
Methadone (multiple dose)
SOF increased 30%; no effect on GS-331007
No dose adjustment
Cyclosporine
SOF increased 4-fold but no effect on GS-331007 No dose adjustment
Tacrolimus No effect on SOF or GS-331007 No dose adjustment
Rifampicin Rifampicin is a potent P-gp inducer* Not recommended
Mathias A 14th Int Workshop on Clin Pharm of HIV Ther Session 5; Kirby B et al 63rd AASLD 2012; Abs 1877. ; Sofosbuvir USPI 2013
Simeprevir
Metabolised by CYP3A4 (Victim) Mild inhibitor of CYP3A4 in intestine
Inhibits OATP1B1 (Perpetrator)
Small Intestines Liver
CYP3A CYP3A UGT
Effect of ARVs on Simeprevir: Victim
Drug Effect on Simeprevir AUC (exposure)
Mechanism/ Recommendation
Darunavir/r
2.6-fold increase but SIM dose 50 mg (DRV increased 18%)
RTV Inhibits CYP3A4
Not recommended
Rilpivirine
No effect No dose adjustment
Efavirenz 70% decrease EFV induces CYP3A4 Not recommended
Raltegravir 11% decrease
No dose adjustment
Tenofovir 14% decrease (TFV increase 18%)
Intestine or renal transport No dose adjustment
Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI
Effect of ritonavir on Simeprevir PK
Ouwerkerk-Mahadevan S et al 15th Int Workshop on Clin Pharm of HIV and HEP Therapy. May 2014
Effect of ARVs on Simeprevir: Victim
Drug Effect on Simeprevir AUC (exposure)
Mechanism/ Recommendation
Darunavir/r
2.6-fold increase but SIM dose 50 mg (DRV increased 18%)
RTV Inhibits CYP3A4
Not recommended
Rilpivirine
No effect No dose adjustment
Efavirenz 70% decrease EFV induces CYP3A4 Not recommended
Raltegravir 11% decrease
No dose adjustment
Tenofovir 14% decrease (TFV increase 18%)
Intestine or renal transport No dose adjustment
Ouwerkerk-Mahadevan S et al, IDSA 2012; Abs 1618; Ouwerkerk-Mahadevan S et al, CROI 2012; Abs 49 ; Simeprevir (Olysio) USPI
Permitted Antiretrovirals with Simeprevir
1st Agent NRTIs
Raltegravir Tenofovir Maraviroc Emtricitabine Rilpivirine Lamivudine
Abacavir
www.hcvguidelines.org.
Drugs Contraindicated/Not Recommended with Simeprevir
Simeprevir Increased Simeprevir Decreased
Erythromycin Carbamazepine Clarithromycin Oxcarbamazine Telithromycin Phenobarbitone Itraconazole Phenytoin Ketoconazole Rifampicin Posaconazole Rifabutin Fluconazole Rifapentine Voriconazole Dexamethasone Milk Thistle St John’s Wort
USPI – accessed April 14th 2014
Effect of Simeprevir on Statins: Perpetrator
Drug Effect of Simeprevir on Statin AUC
Mechanism/ Recommendation
Atorvastatin
2.1-fold increase
CYP3A & OATP1B1 inhibition
Use lowest dose
Rosuvastatin
3.2-fold increase OATP1B1 inhibition Initiate with 5mg
Simvastatin 40% increase CYP3A inhibition Titrate dose carefully
Simprevir (Olysio) USPi 2013
Sofosbuvir and Simeprevir: Interaction Potential
Drug
CYP Activity
Transporters
Interaction Potential
Sofosbuvir (NS5B)
Metabolised by cathepsin A; CES1 and is phosphorylated.
Not metabolised by CYPs
No inhibition of CYP
Transported by P-gp and BCRP
Inhibition (weak) of intestinal P-gp and BCRP
Weak
Simeprevir (NS3/4A)
Metabolised by CYP3A4 Mild inhibitor of
intestinal CYP3A4 No inhibition of hepatic
CYP3A4
Tranported by P-gp Mild inhibitor of
intestinal P-gp Inhibits OATP1B1,
MRP2
Moderate
FDA Antiviral Drugs Advisory Committee Meeting Briefing Document: Simeprevir, October 2013; Simeprevir USPI; Sekar V et al; EASL 2010; Abstract 1076; Mathias A 14th Int Workshop on Clin Pharm of HIV Ther; April 2013; Sofosbuvir USPI.
Daclatasvir
Metabolised by CYP3A4 Transported by P-gp
(Victim) Inhibits P-gp and OATP1B1
(Perpetrator)
Effect of Co-adminstered drugs on Daclatasvir: Victim
Drug Effect on Daclatasvir Recommendation
Atazanavir/r
DCV AUC increased 2.1-fold DCV Cmin increased 3.6-fold
Decrease dose to 30mg
Efavirenz
DCV AUC decreased 32% DCV Cmin decreased 59% Increase dose to 90 mg
Tenofovir No effect No dose adjustment
Omeprazole DCV AUC decreased 18% No dose adjustment
Bifano M et al 2013; 18: 931-941; Bifano M et al; 2013;EASL Abs 794.;
Effect of Daclatasvir on Co-meds: Perpetrator
Drug Effect of Daclatasvir on co-med Recommendation
Sofosbuvir
SOF AUC increased 35%; GS-331007 – no effect
No dose adjustment
Midazolam
MDZ AUC decreased 13% No dose adjustment
Cyclosporine No effect on CsA No dose adjustment
Tacrolimus No effect on TAC No dose adjustment
Oral Contraceptive
No effect on EE; Norgestrel AUC increased 12%
No dose adjustment
Eley T et al. 2013. 8th IWCPHepTHer Abs O-14; Eley T et al. 2013. 8th IWCPHepTHer Abs O-15; Bifano M et al, CROI 2014; Abs 502; Bifano M et al 2011; 62nd AASLD; ABS 1340.
Daclatasvir: Interaction Potential
Drug
CYP/enzyme Activity
Transporters
Interaction Potential
Daclatasvir
(NS5A) Metabolised by
CYP3A4 Does not inhibit major
CYPs
Transported by P-gp
Inhibits OATP1B1; P-gp
Moderate
Bertz R 2013; 14th Int Workshop on Clin Pharm of HIV Ther, Session 5; Bifano M et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther, Abs O-15; Amblard F et al; Bioorg Med Chem Lett 23; 2031-2034.
DAAs in Development
Drug
CYP Activity
Transporters
Interaction Potential
Ledipasvir (NS5A)
Little metabolism Not Inhibitor of CYP or
UGT Not Inducer of CYP or
UGT
Transported by P-gp Inhibits intestinal P-gp
(weak) Inhibits OATP1B1/3
(weak)
Weak
Asunaprevir (NS3/4A)
Metabolised by CYP3A4 Induces CYP3A4 and
inhibits CYP2D6 (weak)
Transported by P-gp, OATP1B1/3
Inhibits P-gp (weak), OATP1B1/3
Moderate
Faldaprevir (NS3/4A)
Metabolised by CYP3A4 Inhibits CYP3A4 (240mg) Inhibits CYP2C9 (240mg) Inhibits UGT1A1
Transported by P-gp, MRP2, OATP1B1
Probable inhibitor of OATP1B1/3; MRP2
Moderate
Eley T et al, 2013, 8th Int Workshop on Clin Pharm of Hep Ther; Abs O-13; Eley T et al, 2011, 62nd AASLD Abs 381; Eley T et al 2012, 7th Int Workshop on Clin Pharm of Hep Ther; Abs O-4; Kirby B et al 2013, 8th Int Workshop on Clin Pharm of Hep Ther; Abs O-20; Mathias A, 14th Int Workshop on Clin Pharm of HIV Ther, Session 5; Kort J 2013; 14th Int Workshop on Clin Pharm of HIV Ther, Session 5; Sane R et al 2011, 46th EASL, Abs 1236; Sabo JP et al, 52nd ICAAC, Abs A-1248;
Abbvie 3D (ABT-450/r; ABT-267; ABT-333)
Drug
CYP/enzyme Activity
Transporters
Interaction Potential
ABT-450 (NS3/4A)
Metabolised by CYP3A4
Inhibits CYP2C8 Inhibits UGT1A1
Transported by P-gp, OATP1B1
Inhibits OATP1B1 and OATP1B3
Moderate
ABT-267 Ombitasvir
(NS5A)
Metabolised by CYP3A4
Inhibits CYP2C8 Inhibits UGT1A1
Transported by P-gp
Moderate
ABT-333 Dasabuvir
(NS5B)
Metabolised by CYP2C8 > CYP3A4 > CYP2D6
Inhibits UGT1A1
Transported by P-gp
Inhibits OATP1B1
Moderate
Abbvie – Personal Communication
RTV has effects on multiple enzymes and transporters – Significant Interactions Formal DDI studies performed with the 3D regimen or 2D (ie ABT450/r + ABT333)
MK-5172 and MK-8742
Drug
CYP/enzyme Activity
Transporters
Interaction Potential
MK-5172 (NS3/4A)
Metabolised by CYP3A4 Inhibits (weak) CYP3A4 Inhibits CYP2C8 Inhibits UGT1A1 (weak)
Transported by P-gp & OATP1B1 Inhibits BCRP?
Moderate
MK-8742 (NS5A)
Metabolised by CYP3A4 Does not Inhibit CYP3A4 Inhibits UGT1A1 (weak)
Transported by P-gp
Transported by OATP1B1 (?)
Moderate
Yeh WW, HEP Dart 2013; Abs 52; Yeh WW et al CROI 2014, Abs 498 & Abs 638.
A stepwise approach to DDI management
OTC: over the counter
Note all co-medications (prescribed, OTC, recreational and herbal products). Always be aware of the unexpected
1
Consult pharmacist and/or online resources 2
Amber
Are drugs necessary ?
Are there alternatives ?
Can DDI be managed ?
Change dose
Establish Monitoring
Plan
Accept risk , discuss with
patient
Stop
Switch
Yes
Yes
Yes
No
No
No
A stepwise approach to DDI management
No clinically significant interaction or interaction not anticipated. Potential interaction that may require close monitoring, alteration of drug dosage or timing of administration. Interaction likely – do not co-administer
Ask key questions. 3
DDIs in the Evolving HCV Treatment Landscape
Polypharmacy is the new ‘norm’
Newer DAAs still have potential to cause DDIs - transporter interactions need to be clarified - use of ritonavir
Shorter treatment courses make these manageable - emphasis should be on harms, not just PK changes - special populations may have increased susceptibility
Acknowledgements Grateful thanks to: The Liverpool Website team: Saye Khoo Sara Gibbons Fiona Marra Catia Marzolini Justin Chiong www.hep-druginteractions Editorial Board